Scavenger receptor BI (SR-BI) is an HDL receptor that regulates HDL cholesterol levels by mediating the delivery of HDL cholesterol esters to the liver. We recently report a novel and potentially clinically important function of SR-BI in protection against LPS-induced death. LPS challenge resulted in 90% fatality of SR-BI null mice, whereas all the wild type littermates survived. More importantly, using a cecum ligation and puncture (CLP) septic model, we demonstrate that CLP treatment induced 100% fatality of SR-BI null mice whereas only 28.5% fatality of wild type littermates. Our findings indicate that SR-BI is critical for survival during sepsis in mice. We hypothesize that SR- BI prevents LPS-induced death by facilitating LPS clearance and suppressing inflammatory reactions. Understanding the mechanism whereby SR-BI prevents LPS- induced death will elucidate a novel mechanism for survival during sepsis and may reveal a strategy for intervention of sepsis. PUBLIC HEALTH RELEVANCE: Sepsis is a severe disease caused by bacterial infection. Sepsis can rapidly develop to septic shock when an overwhelming infection leads to low blood pressure and multi-organs dysfunction. Septic shock is one of the major causes of death that claims over 215,000 lives and costs $16.7 billion per year in America alone. Death rate of septic shock is high, exceeding 50%, due to the poor understanding of the disease and the lack of efficient therapies. Lipopolysaccharides (LPS) play a central role in sepsis. LPS is released by bacteria in sepsis. It stimulates our body to generate too much inflammatory factors which causes tissue damage and death. Great efforts have been made to find effective treatments for sepsis including the application of antibodies to neutralize LPS. However, it proven that simply neutralizing LPS without LPS removal is not protective against LPS toxicity. We recently reported that a protein called SR-BI is highly protective against septic death. The preliminary studies suggest that SR-BI prevents septic death by enhancing the removal of LPS. The purpose of this application is to determine the mechanism of how SR-BI removes LPS, which may provide a novel strategy for the intervention of sepsis.